Acquired hydrocephalus following hypoxic ischemic encephalopathy without intraventricular hemorrhage: A case report.

The most common cause of acquired hydrocephalus in infants is hemorrhage, most often as a consequence of prematurity. Other important causes include neoplasm and infection, usually bacterial meningitis. Hypoxic ischemic encephalopathy (HIE) in term infants usually results in secondary microcephaly. We report an infant with severe HIE at birth treated by therapeutic hypothermia who developed progressive acquired hydrocephalus over 2 months, although no cause of the hydrocephalus was identified. Although hydrocephalus, even intraventricular hemorrhage, is uncommon in term infants with HIE, careful follow-up of the head circumference is important, even if no findings indicating possible causes of hydrocephalus, such as hemorrhage, are detected on ultrasound or magnetic resonance imaging.

Dual-Task Training Combining Cognitive Tasks and Occupations among Japanese Community-Dwelling Older Adults: A Pilot Study.

This study investigated whether dual tasks comprising cognitive tasks and occupations related to daily living can improve the mental and cognitive function of Japanese community-dwelling older adults. Participants included 30 older adults, equally divided into intervention and control groups. The outcome measures were memory, attention, depression, and health-related quality of life. No adverse effects of the intervention were observed in any participant in the intervention group. Logical memory I, logical memory II, and Center for Epidemiologic Studies Depression Scale scores showed a significant interaction. Dual tasks combining cognitive tasks and occupations may help improve delayed recall and alleviate depression. A novel attempt to integrate cognitive stimulation and activities valued by individuals may help mediate age-related cognitive function decline and reduce depressive symptoms in community-dwelling older adults.

Progression-dependent transport heterogeneity of breast cancer liver metastases as a factor in therapeutic resistance.

Metastatic disease is a major cause of mortality in cancer patients. While many drug delivery strategies for anticancer therapeutics have been developed in preclinical studies of primary tumors, the drug delivery properties of metastatic tumors have not been sufficiently investigated. Therapeutic efficacy hinges on efficient drug permeation into the tumor microenvironment, which is known to be heterogeneous thus potentially making drug permeation heterogeneous, also. In this study, we have identified that 4 T1 liver metastases, treated with pegylated liposomal doxorubicin, have unfavorable and heterogeneous transport of doxorubicin. Our drug extravasation results differ greatly from analogous studies with 4 T1 tumors growing in the primary site. A probabilistic tumor population model was developed to estimate drug permeation efficiency and drug kinetics of liver metastases by integrating the transport and structural properties of tumors and delivered drugs. The results demonstrate significant heterogeneity in metastases with regard to transport properties of doxorubicin within the same animal model, and even within the same organ. These results also suggest that the degree of heterogeneity depends on the stage of tumor progression and that differences in transport properties can define transport-based tumor phenotypes. These findings may have valuable clinical implications by illustrating that therapeutic agents can permeate and eliminate metastases of "less resistant" transport phenotypes, while sparing tumors with more "resistant" transport properties. We anticipate that these results could challenge the current paradigm of drug delivery into metastases, highlight potential caveats for therapies that may alter tumor perfusion, and deepen our understanding of the emergence of drug transport-based therapeutic resistance.

E-cadherin expression is correlated with focal adhesion kinase inhibitor resistance in Merlin-negative malignant mesothelioma cells.

Malignant mesothelioma (MM) is an aggressive tumor commonly caused by asbestos exposure after a long latency. Focal adhesion kinase (FAK) inhibitors inhibit the cell growth of Merlin-deficient MM cells; however, their clinical efficacy has not been clearly determined. The aim of this study was to evaluate the growth inhibitory effect of the FAK inhibitor VS-4718 on MM cell lines and identify biomarkers for its efficacy. Although most Merlin-deficient cell lines were sensitive to VS-4718 compared with control MeT-5A cells, a subset of these cell lines exhibited resistance to this drug. Microarray and qRT-PCR analyses using RNA isolated from Merlin-deficient MM cell lines revealed a significant correlation between E-cadherin mRNA levels and VS-4718 resistance. Merlin- and E-cadherin-negative Y-MESO-22 cells underwent apoptosis upon treatment with a low concentration of VS-4718, whereas Merlin-negative, E-cadherin-positive Y-MESO-9 cells did not undergo VS-4718-induced apoptosis. Furthermore, E-cadherin knockdown in Merlin-negative MM cells significantly sensitized cells to VS-4718 and induced apoptotic cell death upon VS-4718 treatment. Together, our results suggest that E-cadherin serves as a predictive biomarker for molecular target therapy with FAK inhibitors for patients with mesothelioma and that its expression endows MM cells with resistance to FAK inhibitors.

The question of whether or not to perform therapeutic hypothermia: A case of neonatal spinal cord injury.

Neonatal spinal cord injury is an extremely rare perinatal complication that often occurs concurrently with hypoxic ischemic encephalopathy (HIE), further complicating diagnosis of spinal cord injury. Although therapeutic hypothermia for moderate to severe HIE is widely recommended in Japan, it is difficult to determine whether it satisfies the neurological findings-related entry criteria in some patients.We describe a female infant with neonatal spinal cord injury after forceps delivery, who underwent therapeutic hypothermia upon diagnosis of HIE. The Apgar scores were 5 at 1 min, 6 at 5 min, and not recorded at 10 min. Blood gas analysis of her umbilical artery was not performed. Since respiratory failure, hypotonia and the absence of primitive reflexes were found at 2 hours after birth, she was initially diagnosed with moderate HIE and underwent a therapeutic hypothermia. Magnetic resonance imaging after therapeutic hypothermia revealed the spinal cord was narrowed from the lower medulla oblongata to the upper cervical cord. Thus she was diagnosed with an upper spinal cord injury at that time.Some patients with neonatal spinal cord injuries satisfy the criteria for therapeutic hypothermia. When neonates with asphyxia present with prolonged respiratory failure and hypotonia, spinal cord injury should be considered in the differential diagnosis. Thus, an early MRI is vital for the diagnosis of spinal cord injury.

Comprehensive molecular exploration identified promoter DNA methylation of the CRBP1 gene as a determinant of radiation sensitivity in rectal cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy (NCRT) for advanced rectal cancer (RC) is a well-evidenced therapy; however, some RC patients have no therapeutic response. Patient selection for NCRT so that non-responsive patients are excluded has been subjective. To date, no molecular markers indicating radiation sensitivity have been reported. METHODS: We irradiated six colorectal cancer (CRC) cell lines and identified HCT116 cells as radiation-sensitive and HCT15 and DLD-1 cells as radiation resistant. Using a microarray, we selected candidate radiation sensitivity marker genes by choosing genes whose expression was consistent with a radiation-resistant or sensitive cell phenotype. RESULTS: Among candidate genes, cellular retinol binding protein 1 (CRBP1) was of particular interest because it was not only induced in HCT116 cells by tentative 10 Gy radiation treatments, but also its expression was increased in HCT116-derived radiation-resistant cells vs parental cells. Forced expression of CRBP1 decreased the viability of both HCT15 and DLD-1 cells in response to radiation therapy. We also confirmed that CRBP1 was epigenetically silenced by hypermethylation of its promoter DNA, and that the quantitative methylation value of CRBP1 significantly correlated with histological response in RC patients with NCRT (P=0.031). CONCLUSIONS: Our study identified CRBP1 as a radiation-sensitive predictor in RC.

The clinical significance of cysteine dioxygenase type 1 methylation in Barrett esophagus adenocarcinoma.

Methylation of cysteine dioxygenase type 1 (CDO1) gene, a tumor suppressor gene, has been studied in various cancers; however, there is no information regarding Barrett esophagus cancer. In this study, the clinical significance of CDO1 methylation in Barrett esophagus adenocarcinoma (BEA) was clarified. CDO1 gene promoter methylation was analyzed for DNA from the patient's specimens using quantitative methylation-specific polymerase chain reaction. Thirty-eight BEA patients who underwent resection were identified between 2000 and 2014. Hypermethylation of CDO1 gene was demonstrated to be frequently recognized even at early stage in BEA by quantitative methylation-specific polymerase chain reaction. In BEA, there is a robust prognostic difference between stage I and stage II/III/IV with regard to 5-year relapse-free survival (P = 0.0016) and 5-year overall survival (P = 0.0024), and the tumor size separated by 7 cm was also a prognostic factor. There was significant difference in CDO1 gene methylation according to the tumor size (P = 0.036). BEA patients with CDO1 gene methylation were shown marginally significantly poorer prognosis (P = 0.054) than otherwise patients. In conclusion, higher CDO1 gene methylation was seen in BEA at earlier stage than in squamous cell carcinoma, and it may account for aggressive phenotype of BEA.

Time to first cigarette and lung cancer risk in Japan.

BACKGROUND: Cigarette smoking is the major cause of lung cancer (LC). Although the time to first cigarette (TTFC) of the day is a distinct indicator of nicotine dependence, little information is available on its possible relation to LC. PATIENTS AND METHODS: This case-control study includes a total of 1572 incident LC cases and 1572 non-cancer controls visiting for the first time the Aichi Cancer Center Hospital between 2001 and 2005. We estimated the odds ratio (OR) and 95% confidence interval (CI) for TTFC using a logistic regression model after adjustment for several potential confounders. RESULTS: TTFC was inversely associated with the risk of LC. This association was consistent across histological subtypes of LC. For all LCs considered among ever smokers and after accurate allowance for smoking quantity and duration, besides other relevant covariates, compared with TTFC >60 min, the adjusted ORs were 1.08 (95% CI, 0.73-1.61) for TTFC of 31-60 min, 1.40 (0.98-2.01) for 6-30 min and 1.86 (1.28-2.71) for within 5 min (Ptrend, < 0.001). Statistically marginally significant heterogeneity by histological subtype was observed (Pheterogeneity, 0.002). CONCLUSIONS: Nicotine dependence, as indicated by the TTFC, is associated with increased risk of LC and is therefore an independent marker of exposure to tobacco smoking.

YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes.

Malignant mesothelioma (MM) shows frequent inactivation of the neurofibromatosis type 2 (NF2) -tumor-suppressor gene. Recent studies have documented that the Hippo signaling pathway, a downstream cascade of Merlin (a product of NF2), has a key role in organ size control and carcinogenesis by regulating cell proliferation and apoptosis. We previously reported that MMs show overexpression of Yes-associated protein (YAP) transcriptional coactivator, the main downstream effector of the Hippo signaling pathway, which results from the inactivation of NF2, LATS2 and/or SAV1 genes (the latter two encoding core components of the mammalian Hippo pathway) or amplification of YAP itself. However, the detailed roles of YAP remain unclear, especially the target genes of YAP that enhance MM cell growth and survival. Here, we demonstrated that YAP-knockdown inhibited cell motility, invasion and anchorage-independent growth as well as cell proliferation of MM cells in vitro. We analyzed genes commonly regulated by YAP in three MM cell lines with constitutive YAP-activation, and found that the major subsets of YAP-upregulating genes encode cell cycle regulators. Among them, YAP directly induced the transcription of CCND1 and FOXM1, in cooperation with TEAD transcription factor. We also found that knockdown of CCND1 and FOXM1 suppressed MM cell proliferation, although the inhibitory effects were less evident than those of YAP knockdown. These results indicate that constitutive YAP activation in MM cells promotes cell cycle progression giving more aggressive phenotypes to MM cells.

Association of a polymorphism of BTN2A1 with type 2 diabetes mellitus in Japanese individuals.

AIMS: We previously showed that the C→T polymorphism (rs6929846) of BTN2A1 was significantly associated with myocardial infarction in Japanese individuals by a genome-wide association study. Given that diabetes mellitus is an important risk factor for myocardial infarction, the association of rs6929846 of BTN2A1 with myocardial infarction might be attributable, at least in part, to its effect on susceptibility to diabetes. The purpose of this study was to examine the relation of rs6929846 of BTN2A1 to Type 2 diabetes mellitus. METHODS: A total of 8650 Japanese individuals from two independent subject panels were examined: Panel A comprised 1141 individuals with Type 2 diabetes and 3161 control subjects and panel B comprised 1664 individuals with Type 2 diabetes and 2684 control subjects. RESULTS: The chi-square test revealed that rs6929846 of BTN2A1 was significantly related to the prevalence of Type 2 diabetes in subject panel A (P = 0.0002) and subject panel B (P=0.006). Multivariable logistic regression analysis with adjustment for age, sex, body mass index and smoking status revealed that rs6929846 was significantly associated with Type 2 diabetes (P = 0.0006; odds ratio 1.25) in all individuals, with the T allele representing a risk factor for this condition. Multiple regression analysis with adjustment for age, sex and body mass index revealed that rs6929846 was significantly (P=0.04) related to blood glycosylated haemoglobin content in control subjects. CONCLUSIONS: BTN2A1 may be a susceptibility gene for Type 2 diabetes in Japanese individuals.

Effect of zinc supplementation on mood states in young women: a pilot study.

The relation of zinc (Zn) nutriture to brain development and function has been elucidated. The purpose of this study is to examine whether Zn supplementation improves mood states in young women. The study used a double-blind, randomized and placebo-controlled procedure. The major outcomes were psychological measures, somatic symptoms and serum Zn. Thirty women were placed randomly and in equal numbers into two groups, and they ingested one capsule containing multivitamins (MVs) or MV and 7 mg Zn daily for 10 weeks. Women who took MV and Zn showed a significant reduction in anger-hostility score (P=0.009) and depression-dejection score (P=0.011) in the Profile of Moods State (POMS) and a significant increase in serum Zn concentration (P=0.008), whereas women who took only MV did not. Our results suggest that Zn supplementation may be effective in reducing anger and depression.

Modified thin abdominal wall flap (glove flap) for the treatment of acute burns to the hands and fingers.

BACKGROUND: Burns to the dorsum of the fingers and hands require debridement and immediate coverage by skin flap at the earliest opportunity. In such situations, the conventional abdominal wall flap is still commonly used as it is a convenient and safe technique, but the foremost problem with this flap is that it is thick and therefore cosmetically unacceptable; it is also functionally not very suitable as the bulkiness of the digits prevents full range of motion. We have developed a modified thin abdominal flap (glove flap) which attains good results. METHODS: Incisions are made in the skin of the abdominal wall only where the hand is to be inserted and where each of the finger tips will be pulled through. The flap is undermined just under the skin to the depth that preserves the subcutaneous vascular networks to create a thin flap. The interdigital area of the flaps should not be undermined so as to create a glove-type pocket. The hand is then inserted in this subcutaneous pocket. After insertion of the injured hand for 10 to 14 days, the flap is resected and attached to the hand. RESULTS: Seven hands of 5 patients were treated by this technique and all the flaps survived safely. The function of the hands and fingers, including range of motion (ROM) in each joint, was successfully salvaged. The reconstructed hands and fingers were aesthetically pleasing. CONCLUSIONS: Although the abdominal wall flap is not a new technique, our modifications to this flap make it possible to acquire functionally and aesthetically better results. Although many excellent techniques such as perforator flaps have been reported recently, we conclude that the abdominal wall flap is still a very useful technique because it can be performed easily, safely and within a short time.

[Thymolipoma associated with myasthenia gravis].

A 42-year-old woman was admitted to our hospital complaining of left ptosis, diplopia, and muscle weakness. A diagnosis of myasthenia gravis was made. Chest roentgenograms, computed tomography (CT), and magnetic resonance imaging (MRI) showed a large anterior mediastial mass and suggested thymolipoma. Extended thymectomy was performed via a median sternotomy. Histopathological examination revealed that the tumor consisted of mature adipose tissue and weighed 1,500 grams, in which thymic tissues with Hassall' s corpuscles but without a germinal center were contained. The histological appearance was compatible with a typical thymolipoma. This is the 24th reported case of thymolipoma associated with myasthenia gravis.

Genetic risk for myocardial infarction determined by polymorphisms of candidate genes in a Japanese population.

BACKGROUND: Although several environmental factors influence the development of myocardial infarction (MI), genetic factors have been shown to contribute to individual susceptibility to this condition. OBJECTIVE: To identify gene polymorphisms that confer susceptibility to MI in order to allow assessment of genetic risk for this condition. METHODS: 3433 unrelated Japanese people (1931 men, 1502 women) were entered into the study. These comprised 1328 subjects with MI (1036 men, 292 women) and 2105 controls (895 men, 1210 women). The genotypes for 40 polymorphisms of 31 candidate genes were determined with a method that combines PCR and sequence-specific oligonucleotide probes with suspension array technology. RESULTS: The chi(2) test revealed that six polymorphisms were significantly (false discovery rate <0.05) related to the prevalence of MI. Further examination by multivariable logistic regression analysis with adjustment for age, sex, body mass index and the prevalence of hypertension, diabetes mellitus and hypercholesterolaemia, in addition to a stepwise forward selection procedure found that the A-->C (Gln1334His) polymorphism (rs3742207) of the collagen type IV alpha-1 gene (COL4A1) and the A-->G polymorphism (rs4804611) of the zinc finger protein 627 gene (ZNF627) were significantly (p<0.05) associated with the prevalence of MI. The variant C allele of COL4A1 was protective against MI, whereas the variant G allele of ZNF627 represented a risk factor for this condition. CONCLUSIONS: Determination of genotypes for COL4A1 and ZNF627 may prove informative for assessment of the genetic risk for MI.

Genetic risk for metabolic syndrome: examination of candidate gene polymorphisms related to lipid metabolism in Japanese people.

BACKGROUND: The aetiology of metabolic syndrome is complex, being determined by the interplay of both genetic and environmental factors. The aim of this study was to identify genetic polymorphisms that confer susceptibility to metabolic syndrome, to allow prediction of genetic risk for this condition. METHODS: The study population comprised 2417 unrelated Japanese subjects (1522 with metabolic syndrome and 895 controls). The genotypes for 44 polymorphisms of 31 candidate genes related to lipid metabolism were determined using a combination of PCR and sequence-specific oligonucleotide probes with suspension array technology. RESULTS: The chi(2) test and subsequent multivariate logistic regression analysis with adjustment for age, sex and smoking status found that the-3A-->G and 553G-->T (Gly185Cys) polymorphisms of APOA5, the 2052T-->C (Val653Val) and 1866C-->T (Asn591Asn) polymorphisms of LDLR, the 13989A-->G (Ile118Val) polymorphism of CYP3A4 and the 1014T-->A polymorphism of C1QTNF5 were significantly (false discovery rate <0.05) associated with the prevalence of metabolic syndrome, with the variant alleles of APOA5 and C1QTNF5 representing risk factors for and those of LDLR and CYP3A4 being protective against this condition. Serum levels of triglycerides and high-density lipoprotein (HDL) cholesterol differed significantly (p<0.05) among APOA5 genotypes; the serum level of HDL cholesterol differed among LDLR genotypes; and the fasting plasma glucose level and body mass index differed between CYP3A4 and C1QTNF5 genotypes, respectively. CONCLUSIONS: APOA5, LDLR, CYP3A4 and C1QTNF5 are susceptibility loci for metabolic syndrome in Japanese people. Genotypes for these polymorphisms may prove informative for prediction of genetic risk for metabolic syndrome.

[Usefulness of dynamic computed tomography for the diagnosis of mediastinal hemangioma].

An asymptomatic 59-year-old female was admitted with an abnormal shadow on her chest radiography. Chest computed tomography (CT) revealed a mass measuring 20 mm in the anterior mediastinum. At the arterial phase on dynamic contrast-enhanced CT (dynamic CT), the pattern of "peripheral puddles", defined as discrete well-defined peripheral enhancing globles, was found in the mass. The tumor was completely resected via a median sternotomy, and was histopathologicaly diagnosed as hemangioma. In this case, dynamic CT was very useful for the preoperative diagnosis, and then the enhancement pattern of "peripheral puddles" on dynamic CT may be a conclusive finding for the diagnosis of mediastinal hemangiomas.

[Surgical treatment for adrenal metastasis from lung cancer].

Several long-term survivors after surgical resection for a solitary adrenal metastasis from non-small cell lung cancer (NSCLC) have been reported in case reports and case series with a small number of patients. We have experienced 6 cases of patients who had adrenalectomy (ADR) for a metastasis from NSCLC. The median survival time (MST) after ADR was 24 months, and there was only 1 case of 3-year survivor. To elucidate the surgical indication and the prognostic factors of patients with a solitary adrenal metastasis from NSCLC, we analyzed 104 patients including our 6 patients who had ADR for a metastasis from NSCLC. The MST after ADR and 5-year survival were 24 months and 31%, respectively. Univariate and multivariate analysis demonstrated that lymph node metastasis at the surgery for primary lung cancer was the only significant and independent predictor of poor survival in patients after ADR. The results suggest that aggressive surgical treatment of a solitary adrenal metastasis from NSCLC may be effective when a patient have N0 disease.

[Pulmonary pleomorphic carcinoma; report of a case].

We report a case of a 64-year-old man with pleomorphic carcinoma of the lung and thymic cyst. He was admitted to our hospital because of an abnormal shadow observed on chest X-ray. Computed tomography (CT) showed a mass lesion located in the right upper lobe and a non-invasive anterior mediastinal tumor adjacent to the left brachiocepharic vein. On enhanced CT, the lung mass showed central low-attenuation areas with a substantial enhancement in the periphery. Preoperative transbronchial blushing cytology of the mass revealed adenocarcinoma. With a diagnosis of primary lung cancer (cT3N0M0) and mediastinal tumor, an operation was performed through a median sternotomy. The mediastinal tumor was excised and a right upper lobectomy and were also accomplished, because the lung tumor did not show adhesion or pleural invasion. Histopathologic examination of the resected specimen revealed that the lung tumor composed of a mixture of spindle and giant cell features and contained a component of adenocarcinoma and squamous cell carcinoma. This finding yielded a pathological diagnosis of pleomorphic carcinoma (pT2N0M0). The mediastinal tumor was diagnosed as thymic cyst. The postoperative course was uneventful, and he is currently well 6 months after surgery.

Dual inhibition of the epidermal growth factor and vascular endothelial growth factor phosphorylation for antivascular therapy of human prostate cancer in the prostate of nude mice.

BACKGROUND: Androgen-independent prostate cancer (PCa) may be susceptible to modulation of the tumor microenvironment. We determined whether a dual tyrosine kinase inhibitor (AEE788) of the epidermal growth factor receptor (EGF-R) and vascular endothelial growth factor receptor (VEGF-R) combined with chemotherapy can produce therapy of human PCa in nude mice. METHODS: PC-3MM2 human PCa cells were injected into the prostate of nude mice. Three days later, the mice were randomized into four groups: saline control, paclitaxel, AEE788, and AEE788 and paclitaxel. The mice were treated for 5 weeks and necropsied. Tumor incidence, weight, and incidence of lymph node metastasis were recorded. Tumor tissue was analyzed immunohistochemically. RESULTS: Treatment of mice with AEE788 or AEE788 plus paclitaxel significantly decreased tumor incidence, total tumor weight, and incidence of lymph node metastasis. AEE788 treatment alone or in combination with paclitaxel inhibited the phosphorylation of EGF-R and VEGF-R on tumor cells and tumor-associated endothelial cells. Therapeutic efficacy correlated with an increase in apoptosis of tumor cells and tumor-associated endothelial cells. CONCLUSION: Blockade of EGF-R and VEGF-R signaling pathways coupled with chemotherapy suppressed the progressive growth and metastasis of human PCa cells growing orthotopically in nude mice.